FARP2 triggers signals for Sema3A-mediated axonal repulsion
FARP2 triggers signals for Sema3A-mediated axonal repulsion
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DOI：
10.1038/nn1596
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发表时间：
2005-12-01
影响因子：
25
通讯作者：
Kikutani, H
中科院分区：
文献类型：
--
作者：
Toyofuku, T;Yoshida, J;Kikutani, H
Sema3A 是一种典型的信号蛋白，通过激活包含神经毡蛋白-1 作为配体结合亚基和丛蛋白-A1 作为信号转导亚基的受体复合物，充当轴突的化学排斥剂或化学引诱剂。然而，Sema3A 刺激后如何触发 plexin-A1 下游信号尚不清楚。在这里，我们表明，在存在 Neuropilin-1 的情况下，含有鸟嘌呤核苷酸交换因子 (GEF) FARP2 的 FERM 结构域直接与 plexin-A1 结合。 Sema3A 与神经毡蛋白-1 结合诱导 FARP2 从 plexin-A1 解离，导致 FARP2 的 Rac GEF 活性激活、Rnd1 募集到 plexin-A1 以及 R-Ras 下调。同时，FARP2 的 FERM 结构域从 talin 中隔离磷脂酰肌醇磷酸激酶 I 型同工型 PIPKI gamma 661，从而抑制其激酶活性。这些活性是 Sema3A 介导的轴突生长排斥和神经元粘附抑制所必需的。因此，我们得出结论，FARP2 是参与神经元生长锥对 3 类信号蛋白反应的关键分子。
Sema3A, a prototypical semaphorin, acts as a chemorepellent or a chemoattractant for axons by activating a receptor complex comprising neuropilin-1 as the ligand-binding subunit and plexin-A1 as the signal-transducing subunit. How the signals downstream of plexin-A1 are triggered upon Sema3A stimulation, however, is unknown. Here we show that, in the presence of neuropilin-1, the FERM domain - containing guanine nucleotide exchange factor (GEF) FARP2 associates directly with plexin-A1. Sema3A binding to neuropilin-1 induces the dissociation of FARP2 from plexin-A1, resulting in activation of FARP2' s Rac GEF activity, Rnd1 recruitment to plexin-A1, and downregulation of R-Ras. Simultaneously, the FERM domain of FARP2 sequesters phosphatidylinositol phosphate kinase type I isoform PIPKI gamma 661 from talin, thereby inhibiting its kinase activity. These activities are required for Sema3A-mediated repulsion of outgrowing axons and suppression of neuronal adhesion. We therefore conclude that FARP2 is a key molecule involved in the response of neuronal growth cones to class-3 semaphorins.